KR20020073132A - Use of adatanserin for the treatment of neurodegenerative conditions - Google Patents

Abstract

Adatanserine is useful for treating neurodegenerative diseases, chronic pain and other diseases associated with dysfunctional glutamate release. Methods for treating such disorders include administering a therapeutically effective amount of adatanserine or a pharmaceutical salt thereof to a patient in need thereof.

Description

Use of adatanserin for the treatment of neurodegenerative conditions

Glutamate is a major neurotransmitter in the central nervous system and plays an important role in neuroplasty. As such, excessive extracellular levels of glutamate are acute neurodegenerative diseases such as stroke, transient ischemic attacks and spinal cord / brain trauma, as well as epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, AIDS dementia and retinal diseases It is associated with the pathophysiology of chronic neurodegenerative diseases such as Holt, WF et al., Glutamate in Health and Disease: The Role of Inhibitors. In: Neuroprotection in CNS Diseases. Bar, P. R. and Beal, M. F., ed., Marcel Dekker, Inc., New York 1997, pp. 87-199; Engelsen, B. A. et al., Alterations in Excitatory Amino Acid Transmitters in Human Neurological Disease and Neuropathology. In: Neurotoxicity of Excitatory Amino Acids. Guidotti, A., ed., Raven Press Ltd., New York 1990, pp. 311-332; Ince, P. G. et al., The Role of Excitotoxicity in Neurological Disease. Res. Contemp. Pharmacother. 1997, 8, 195-212; Meldrum, B. S. The Glutamate Synapse as a Therapeutical Target: Perspective for the Future. Prog. Brain. Res. 1998, 441-458. Compounds that inhibit release of glutamate may be useful for the treatment of chronic diseases caused by glutamate dysfunction, such as chronic neurodegeneration, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, schizophrenia, AIDS dementia and retinal disease It is expected.

In addition, compounds that inhibit and reduce the release of glutamate have been shown to be potent neuroprotective agents for the treatment of ischemia resulting from stroke, transient ischemic attacks and brain / spinal trauma [Ref. Koroshetz, WJ and Moskowitz, MA, Emerging Treatment for Stroke. in Humans. Trends in Pharmacol. Sci 1996, 17, 227-233; Dunn, C. D. R. Stroke: Trends, Treatments and Markets. Scrip Reports, PJB Publications, Richmond 1995].

Ischemia can also be caused by anoxia and hypoglycemia resulting from surgery that requires stopping blood flow for a period of time. Arrowsmith, J. E. et al., Neuroprotection of the Brain During Cardiopulmonary Bypass. A Randomized Trial of Remacemide During Coronary Artery Bypass in 171 Patients, Stroke 1998, 29, 2357-2362, and references cited therein]. It is also expected that compounds that inhibit or attenuate release of glutamate exhibit neuroprotective and anti-ischemic activity under these conditions.

Excess levels of glutamate have been shown to be associated with chronic neuropathic or persistent pain, including fibritis, herpes neuralgia, reflex sympathetic dystrophy and diabetic peripheral neuropathy [Meldrum, B. S., supra].

Serotonin 5-HT _1A receptors are located in areas of the brain that are highly sensitive to ischemia, such as the hippocampus and cerebral cortex. Activation of this receptor subtype results in neuronal hyperpolarization and inhibition of neuronal activity associated with it [DeVry, J., 5-HT _1A Agonists: Recent Developments and Controversial Issues, Psychopharmacology, 1995, 121, 1-26 ].

5-HT _1A receptor agonists and partial agonists have been shown to reduce glutamate release, mostly through activation of the 5-HT _1A receptor located at the glutamate terminus (Matsuyama, S. et al., Regulation of Glutamate Release via NMDA and 5-HT _1A Receptors in Guinea Pig Dentate Gyrus. Brain Res. 1996, 728, 175-180. Several 5-HT _1A agonists and partial agonists have been shown to exhibit neuroprotective properties in vivo [Refry, J. et al., BAY × 3702, Drugs of the Future 1997, 22, 341- 349, and references cited therein], 5-HT _1A receptor agonists have various effects on neuronal survival [Ref. Bode-Greuel, KM et al., Serotonin (5-HT _1A ) Receptor Agonists as Neuroprotective Agents in Cerebral Ischemia. In: Pharmacology of Cerebral Ischemia 1990, Krieglstein, J. and Oberpichler, H., ed., Wissenschaftliche Verlagsgesellschaft mgH, Stuttgart (1990), pp. 485-491).

Several serotonin 5-HT ₂ antagonists have also been shown to have neuroprotective effects. (S) -Emofamil [Ref. Lin, BW er al., (S) -Emopamil Protects against Global Ischemic Brain Injury in Rats. Stroke 1990, 21, 1734-1739; Nakayuama, H. et al., (S) -Emopamil, a Novel Calcium Channel Blocker and Serotonin S2 Antagonist, Markedly reduces Infarct Size Following Middle Cerebral Artery Occlusion in the Rat. Neurology 1989, 38, 1667-1673] and naphthydrofuryl [Krieglstein, J. et al., Naftidrofuryl Protects Neurons Against Ischemic Damage. Eur. Neurology. 1989, 29, 224-228; Fujikura, H. et al., A Serotonin S2 Antagonist, Naftidrofuryl, Exhibited a Protective Effect on Ischemic Neuronal Damage in the Gerbi. Brain Res. 1989, 494, 387-390, provide neuroprotective effects in animal models of cerebral ischemia.

DE 4138756 shows that the aminomethylchroman derivative, a 5-HT _1A receptor agonist, protects the neuroprotective activity of 5-HT ₂ receptor antagonists such as ketanserin, ritanserin and other 4-fluorophenyl derivatives. Teaching increasing [Ref. Bode-Greuel, K., Kombination mit Neuroprotektiver Wirkung. German Patent DE 4,138,756, 5/27/93.

Simultaneous administration of ipsapirone, a compound with 5-HT _1A agonist activity, and ketanserin, a compound with 5-HT ₂ antagonist activity, was more effective in an ischemic animal model than for each single agent. Provide neuroprotection [Ref. Bode-Greuel, KM et al., Serotonin (5-HT _1A ) Receptor Agonists as Neuroprotective Agents in Cerebral Ischemia. In: Pharmacology of Cerebral Ischemia 1990, Krieglstein, J. and Oberpichler, H., ed., Wissenschaftliche Verlagsgesellschaft mgH, Stuttgart (1990), pp. 485-491].

Neuroprotective activity of a compound may contribute to one or more aspects of the receptor activity profile. For example, it is assumed that the 5-HT _1A agonist BAY R 1531 has a low binding affinity for 5-HT ₂ , D2 and sigma receptors, which may play an important role in neuroprotective potency as well as 5-HT _1A activity. [Ref. Bode-Grueul, supra].

Approximately 5-6 million Americans suffer from chronic or acute neurodegenerative diseases. Therefore, there is a need for effective compounds for the treatment and prevention of neurodegenerative conditions. The present invention provides useful agents for the treatment and prevention of neurodegenerative diseases.

1 shows graphically the effect of adatanserine on azide-induced ischemic outflow of glutamate in rat hippocampal sections. The effects of the three concentrations of adatanserine 10 (down diagonal), 100 (up diagonal) and 1000 nM (check) were compared with the control (black). At concentrations of 100 and 1000 nM, statistically significant decreases (72% and 71%, respectively) were observed for glutamate concentrations.

The present invention relates to N- [2- [4- (2-pyrimidinyl) -1-piperazinyl] ethyl] tricyclo [3.3.1.13,7] decane-1-carboxamide or adatanserine and pharmaceuticals It relates to novel therapeutic uses of salts thereof. The present invention provides novel methods of treating chronic and acute neurodegenerative diseases in mammals in need of treatment of chronic and acute neurodegenerative diseases.

Suitable salts include hydrochloric acid, hydrobromic acid, sulfonic acid, sulfuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, methanesulfonic acid, acetic acid, propionic acid, tartaric acid, citric acid, lactic acid, malic acid, It can be prepared from pharmaceutically acceptable organic and inorganic acids such as mandelic acid, cinnamic acid, palmitic acid, itaconic acid and benzenesulfonic acid.

Adatanserine and pharmaceutical salts thereof can also be used to mediate or inhibit glutamate activity associated with diseases known as chronic, neuropathic or persistent pain.

U.S. Patent 5,380,725 and U.S. Patent 5,482,940 disclose N- [2- [4- (2-pyrimidinyl) -1-piperazinyl] ethyl] tricyclo [3.3.1.13,7] decane-1-car Copyamide or adatanserine, methods of preparation thereof and some uses thereof. The published uses are for the treatment of psychosis, such as depression, anxiety, paranoia and schizophrenia, reduction of overweight and reduction of excess ethanol consumption. Said patent is incorporated herein by reference.

Dysfunctional glutamate release, and particularly excess glutamate release, is associated with the pathophysiology of acute and chronic neurodegenerative diseases. Adatanserine has been found to inhibit the release of glutamate and is therefore useful for the treatment and prevention of acute and chronic neurodegenerative diseases in order to alleviate or eliminate symptoms. As used herein, a therapeutically effective amount is an amount sufficient to provide some degree of neuroprotection, or to treat, inhibit or alleviate the symptoms associated with neurodegenerative, chronic pain, or excessive or dysfunctional glutamate release.

Chronic neurodegenerative diseases are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, AIDS dementia and retinal disease.

Acute neurodegenerative diseases include, but are not limited to stroke, head or spinal cord trauma and asphyxia.

Strokes include acute thromboembolic strokes, local and systemic ischemia, transient cerebral ischemic attacks and other cerebrovascular disorders associated with cerebral ischemia.

Other acute neurodegenerative conditions are associated with head trauma, spinal cord trauma, general anoxia, hypoxia including fetal hypoxia, hypoglycemia, hypotension, as well as similar injuries seen during the progression of disinfection, hyperfusion and hypoxia.

The invention may also be useful in a range of events, including during surgery and especially cardiac surgery, cranial bleeding events, perinatal choking, cardiac arrest and convulsions, especially when the blood flow to the brain is stopped for a period of time.

Chronic, neuropathic or persistent pain includes fibritis, herpes neuralgia, reflex sympathetic dystrophy and diabetic peripheral neuropathy.

A therapeutically effective amount of adatanserine or a pharmaceutical salt thereof may be administered orally or parenterally, alone or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances that may act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrants or encapsulating agents. In powders, the carrier is a finely divided solid which is mixed with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets may contain up to 99% active ingredient. Suitable solid carriers are, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, carboxymethyl cellulose sodium, polyvinylphyllolidine, low melting waxes and ion exchange resins It includes. Liquid carriers can be used to prepare solvents, suspensions, emulsions, syrups and elixirs. The active ingredients of the present invention may be dissolved or suspended in pharmaceutically acceptable liquid carriers such as water, organic solvents, mixtures of the two or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers or osmo-control agents. Suitable examples of liquid carriers for oral and parenteral administration include water (especially those additives such as those containing cellulose derivatives, preferably carboxymethyl cellulose sodium solution), alcohols (monohydric and polyhydric alcohols, For example glycols), and derivatives thereof, and oils (eg, fractionated coconut oil and arachis oil). Also for parenteral administration, the carrier may be an oil ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration. Liquid pharmaceutical compositions that are sterile solutions and suspensions can be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration can be in liquid form or in the form of a solid composition. Preferably, pharmaceutical compositions containing the present compounds are in unit dosage form such as, for example, tablets or capsules. In this form, the composition is subdivided into unit dosages containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged composition such as a sachet containing a packaged powder, a vial, an ampoule, a prefilled syringe or a liquid. Alternatively, the unit dosage form may be, for example, the capsule or the tablet itself, or may be in the form of a package in any suitable number of such compositions. The therapeutically effective amount used in the treatment of a particular disease or condition should be determined subjectively by the attending physician. In general, a human may be administered a daily dose of about 100 mg to 1,500 mg per day, preferably about 300 mg to about 1,200 mg per day, more preferably about 500 mg to 1,000 mg per day. Variables related to determining the appropriate therapeutic dosage include the particular condition (s) to be treated and the height, age and response pattern of the patient.

As agents for the treatment and prevention of neurodegenerative diseases, the efficacy of adatanserine and pharmaceutical salts thereof is demonstrated by standard experimental procedures.

Example 1

Reduction of Ischemic Outflow of Glutamate in Rat Hippocampal Sections

Adatanserine was evaluated for its ability to reduce azide-induced ischemic outflow in rat hippocampal sections. Three Kreb buffers were used for the experiment. Normal Kreb buffer consisted of a solution containing 122 mM NaCl, 3 mM KCl, 24 mM NaHCO ₃ , 10 mM glucose, 0.315 mM K ₂ HPO ₄ , 1.2 mM MgSO ₄ , 4 mM CaCl ₂ . Glucose-free creep buffer was similar to normal buffer except no glucose was added. Ischemic Kreb buffer was a glycemic solution containing various concentrations of sodium azide (0-30 mM).

Rat hippocampus was cut on cold plates and suspended in ice cold oxygenated normal Kreb buffer. Tissues were ground to 350 microns in a McIlwain tissue mill and then resuspended in ice cold normal Kreb buffer and washed three times. About 80 mg of tissue (one whole hippocampus) in 130 mL solution was added to the wells of the Brandel superperfusion apparatus. Samples were perfused with oxygenated normal Kreb buffer and equilibrated for 30 minutes at a flow rate of 0.4 mL / min. Three 10 minute fractions were harvested and then ischemia was induced by application of ischemic Kreb buffer (containing sodium azide). Three additional 10 minute fractions were then collected. For experiments testing the test compound, the drug was added to one fraction dissolved in glycemic-free Krebs buffer prior to ischemia induction. Amino acid concentrations were analyzed by reverse phase HPLC on a catacolamine column (Keystone Scinetific, 150 × 3 mm) using a 0.05 M acetate / methanol gradient. Alpha-aminoadipic acid was used as internal standard. Amino acids were derivatized with naphthalene-2,3-dicarboxaldehyde and visualized by detection by fluorescence measurement. . J. Chromatogr. B 1997, 694, 1204-1212. The amino acid concentrations of the first three equilibrium fractions were averaged and all subsequent values were expressed as percentage of the mean using the area under the curve for each individual experiment obtained with the trapezoidal method. The results are shown in FIG.

As shown in FIG. 1, adatanserine significantly reduced azide-induced ischemic outflow of glutamate in rat hippocampal sections. Concentrations of 100 nM and 1 μM reduced the release of glutamate by 72% and 71%, respectively.

The present invention may be embodied in other specific forms without departing from its spirit and essential attributes, and therefore, reference should be made to the appended claims rather than to the foregoing specification, as indicating the scope of the invention.

Claims (37)

A method of treating neurodegenerative disease, comprising administering a therapeutically effective amount of adatanserine or a pharmaceutical salt thereof to a patient in need thereof. The method of claim 1, wherein the neurodegenerative disease is chronic. The method of claim 2, wherein the neurodegenerative disease is Alzheimer's disease. The method of claim 2, wherein the neurodegenerative disease is Huntington's disease. The method of claim 2, wherein the neurodegenerative disease is Parkinson's disease. The method of claim 2, wherein the neurodegenerative disease is AIDS dementia. The method of claim 2, wherein the neurodegenerative disease is amyotrophic lateral sclerosis. The method of claim 2, wherein the neurodegenerative disease is retinal disease. The method of claim 2, wherein the neurodegenerative disease is epilepsy. The method of claim 1, wherein the neurodegenerative disease is acute. The method of claim 10, wherein the neurodegenerative disease is stroke. The method of claim 11, wherein the stroke is acute thromboembolic stroke. The method of claim 11, wherein the stroke is focal ischemia. The method of claim 11, wherein the stroke is global ischemia. The method of claim 11, wherein the stroke is a transient ischemic attack. The method of claim 10, wherein the neurodegenerative disease is ischemia resulting from surgical techniques related to prolonged stopping of blood flow to the brain. The method of claim 10, wherein the neurodegenerative disease is head trauma. The method of claim 10, wherein the neurodegenerative disease is spinal cord trauma. The method of claim 10, wherein the neurodegenerative disease is hypoxia. The method of claim 19, wherein the hypoxia is fetal hypoxia. A method of treating chronic pain, comprising administering a therapeutically effective amount of adatanserine to a patient in need thereof. The method of claim 21, wherein the pain is diabetic peripheral neuropathy. The method of claim 21, wherein the pain is selected from fibritis, herpes neuralgia and reflex sympathetic dystrophy. A method of neuroprotection comprising administering a therapeutically effective amount of adatanserine to a patient in need of neuroprotection. Use of adatanserine or a pharmaceutical salt thereof in the manufacture of a medicament for the treatment of neurodegenerative diseases. The use of claim 25, wherein the neurodegenerative disease is chronic. The use according to claim 25 or 26, wherein the neurodegenerative disease is Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS dementia, amyotrophic lateral sclerosis, retinal disease or epilepsy. The use of claim 25, wherein the neurodegenerative disease is acute. The use of claim 28, wherein the neurodegenerative disease is stroke. The use of claim 29, wherein the stroke is an acute thromboembolic stroke, focal ischemia, systemic ischemia or transient ischemic attack. The use of claim 28, wherein the neurodegenerative disease is ischemia resulting from surgical techniques related to prolonged arrest of blood flow to the brain. The use of claim 28, wherein the neurodegenerative disease is head trauma, spinal cord trauma or hypoxia. 33. The use of claim 32, wherein the hypoxia is fetal hypoxia. Use of adatanserine or a pharmaceutical salt thereof in the manufacture of a medicament for the treatment of chronic pain. 35. The use of claim 34, wherein the pain is diabetic peripheral neuropathy. 35. The use of claim 34, wherein the pain is selected from fibritis, herpes neuralgia and reflex sympathetic dystrophy. Use of adatanserine or a pharmaceutical salt thereof in the manufacture of a medicament for the preparation of neuroprotection.